Swallowable capsule, system and method for measuring gastric emptying parameters

ABSTRACT

Embodiments provide devices, systems and methods for measuring a gastric emptying (GE) parameter (GEP). Many embodiments provide a swallowable capsule having three electrodes one covered by a coating which remains in the stomach but is degraded in the small intestine (SI). The electrodes are coupled to circuitry such that when the capsule is in the stomach, current flow occurs between the first two electrodes generating a first signal and in the SI current flow occurs between the second and now uncovered third electrode generating a second signal. These two signals can be transmitted and analyzed externally or by an internal controller to determine a GEP e.g., GE time. The patient may wear an external device configured to receive and analyze the signals to determine GE time. Embodiments of the invention may be used to diagnose gastroparesis and provide patient&#39;s information on when to eat meals or administer insulin after eating.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/006,093, filed Jun. 12, 2018, now U.S. Pat. No. ______; which claimsthe benefit of priority of U.S. Provisional Patent Application Ser. No.62/518,246, filed Jun. 12, 2017; the contents of which are fullyincorporated herein by references for all purposes.

BACKGROUND OF THE INVENTION 1. Field of the Invention

Embodiments described herein relate to devices, systems and methods formeasuring physiologic parameters of the gastro-intestinal system. Morespecifically embodiments of the invention relate to devices, systems andmethods for measuring gastric emptying parameters such as gastricemptying time.

There are a number of conditions which can affect the proper digestionand function of the gastro-intestinal tract of a human or other mammal.One of them, gastroparesis, also known as delayed gastric emptying, is acondition characterized by multiple symptoms, including nausea,vomiting, bloating, abdominal pain or discomfort and early satiety.Diagnosing gastroparesis is traditionally determined from a combinationof symptom assessment and gastric emptying scintigraphy. In particular,this method can be used to measure gastric emptying time, or the time ittakes for food to be emptied from the stomach into the small intestineafter being eaten. Gastro duodenal manometry may also be performed toprovide further evidence of the condition. Gastro duodenal manometry isan invasive, catheter-based system in which a manometry probe isinserted through a patient's nose or mouth into the GI tract. Themanometry probe usually has a suite of pressure sensors located at fixedpositions along its length. These pressure sensors detect and sendcontraction amplitude and frequency data through connected Wires to anexternal recording device. For placement of the probe, this technique isuncomfortable for the patient and requires the patient to be sedated andphysically connected to the detector. Besides being highlyuncomfortable, the manometry measurement system directly impacts thenormal functioning of the patient which may skew the manometry results.

Thus for the reasons above, there is a need for improved systems andmethod for measurement of gastric emptying time as well as a means fordiagnosing gastroparesis.

SUMMARY OF THE INVENTION

Embodiments of the invention provide devices, systems and methods formeasuring a gastric emptying parameter (GEP) such as gastric emptyingtime. Many embodiments provide a swallowable capsule having threeelectrodes one covered by a coating which remains in the stomach but isdegraded in the small intestine (SI). The electrodes are coupled tocircuitry such that when the capsule is in the stomach, current flowoccurs between the first two electrodes generating a first signal and inthe SI current flow occurs between the second and now uncovered thirdelectrode generating a second signal. These two signals can betransmitted and analyzed by an external device or an internal controllerto determine a gastric emptying time or other gastric emptyingparameter. The patient may wear an external device configured to receiveand analyze the two signals and provide the patient and/or medicalprovider with information on gastric emptying time or other gastricemptying parameter.

Embodiments of the invention are particularly useful in diagnosingpatients with gastroparesis or related conditions and providing thosepatients with information on eating patterns, e.g., portion sizes andtimes between portions, so as to minimize the adverse symptoms of thecondition (e.g., nausea). They may also be used to provide patients whohave glucose regulation disorders such diabetes with information on whento administer their insulin (or other glucose regulating compound) afterthey eat a meal.

In a first aspect, embodiments of the invention provide swallowabledevices such as swallowable capsules for the measurement of gastricemptying time or other gastric emptying parameter. An embodiment of sucha capsule comprises a capsule body sized to be swallowed and passthrough the intestinal track of a patient. The capsule body defines acapsule interior for positioning of one or more components of thecapsule. The capsule body desirably comprise various biocompatiblepolymers known in the art which are not broken down in the GI tract,suitable examples including polycarbonate. The capsule body may alsohave imaging markers such as radio-opaque or echogenic markers so as tobe visible under fluoroscopy or ultrasound. Also the entire capsule bodymay be from radio-opaque or echogenic materials or otherwise comprisesuch materials. Two or more electrodes may be positioned on the capsulebody in various arrangements so as to couple to and have current flowthrough the fluids present in the organs of the GI tract such as thosein the stomach or small intestine. The electrodes may comprise one ormore biocompatible conductive metals known in the medical device artssuch as stainless steel or gold alloys and they may be attached tocapsule body using various biocompatible adhesives. In specificembodiments, at least a first, second and third electrodes disposed aredisposed on an outer surface of the capsule body. In preferredembodiments, the electrodes are linearly aligned with respect to alongitudinal axis of the capsule, though radial alignments andnon-aligned configurations are also considered. Also preferably, theyare spaced equidistantly (e.g., in range from about 1 mm to 10 mm), sothat the distance between first and second electrodes is about the sameas between the second and third electrode. However, in some embodimentnon-equidistant configurations may be used. For example, in someembodiments, the second and third electrodes can be spaced closer toprovide for reduced resistance for the flow of electrical currentbetween the second and third electrodes when the device is in the smallintestine which may contain less conductive fluids/medium for completinga circuit between electrodes vs the stomach which contains moreconductive fluids by virtue of its acid and higher fluid content.

An enteric electrically insulative coating is disposed over a portion ofthe capsule body outer surface including the third electrode. Thecoating is configured to protect and electrically insulate the thirdelectrode while in the stomach and degrade in response to a selected pHin the small intestine to expose the third electrode to the fluids inthe small intestine. The capsule body interior contains a first circuitelectrically coupled to the first and second electrodes and a secondcircuit coupled to the second and third electrodes. A controller, alsodisposed in the capsule body, is electrically coupled to both circuits.The circuits typically include an operational amplifier (opamp) and atleast three resistors, which may be arranged in a voltage dividerconfiguration. The opamp receives an input signal from a node of therespective circuit including the first or third electrodes, amplifies itand sends the output signal as an input signal to the controller. Theresistors may have values above 1 to 10 mega Ohm. The circuits may alsoinclude a capacitor to ensure that current which flows between theelectrodes in the stomach or small intestine is an AC current. Thecircuits also receive a driver input voltage from the controller.

The circuits can be configured to perform one or more functions used inmeasuring GET or other GE parameter. In particular, the first circuit isconfigured to generate a first input signal when there is current flowbetween the first and second electrodes and the second circuit isconfigured to generate a second input signal based when there is currentflow between the second and third electrodes. As is explained below,current flow occurs in the first circuit when the first and secondelectrodes come into contact with conductive fluids in the stomach suchas stomach acids. When this happens, the first circuit starts togenerate an input signal to the controller which provides an indicationof when the capsule has reached the stomach after being swallowed.Similarly, current flows in the second circuit after the insulativecoating degrades in the small intestine and the second and thirdelectrodes come into contact with conductive fluids in the smallintestine. When this happens, the second circuit generates an inputsignal to the controller which provides an indication of when thecapsule has reached the small intestine. Information from these twosignals, including their start times, can then be used to determinegastric emptying time or another gastric emptying parameter. Inparticular embodiments the start times can be determined using a clockdevice integral or otherwise coupled to the controller. In particular,the start time of the first input signal can be subtracted from thestart time of the second signal to arrive at gastric emptying time. Inparticular embodiments, allowances can be made for the estimated time ittakes for the enteric coating to degrade in the small intestine, as wellother factors. Such allowances can be incorporated into a module fordetermination of gastric emptying time which may be resident on acontroller of an external device or the controller in the capsule.

The controller, which may correspond to a microprocessor or analoguedevice, is coupled to both circuits as well as power source such as alithium ion or other chemical storage battery. The controller may alsoinclude or be coupled to a transmitter such as an RF transmitter, fortransmitting signals encoding information from the controller, (e.g.,GET) to a receiver on an external device. In some embodiments thecontroller may include a low power RF generator and the transmitter maycorrespond to a power amplifier which amplifies the low power RF signalcoming from the controller.

The controller may be configured to perform a number functions eithervia hardware or software. In particular it may be configured to generateand/or utilize a clock signal for determining the start times of thefirst and second signals. The clock signal may be single phase ormultiphase. Also in some embodiments, the clock signal can be generatedby an analog-to-digital converters. The controller will also typicallybe configured to generate a driver signal sent to the second electrodeand receive the signals from the first and second circuits when currentis flowing through them. Typically, the driver signal is in the form ofan AC voltage with very low amperage in the milliamp range, morepreferably in the micro-amp and voltage in the range from 0.5 to 2 voltswith other ranges contemplated. The controller is further configured togenerate a first output signal in response to the first input signalfrom the first circuit and a second output signal in response to thesecond output signal from the second circuit. The respective outputsignals will typically be in AC form and configured for transmission bythe RF or other transmitter integral to or otherwise coupled to thecontroller. These signals may be generated by the controller itself or asignal generator electrically coupled to the controller. In particularembodiments, the output signals may correspond to distinctive chirpsignals known in the signal processing arts. In one particularembodiment, the first output signal may correspond to an up chirp signaland the second signal a down chirp signal. The controller can alsocontrol how long a respective output signal is generated once it starts.For example, it can stop the first output signal after a selected periodof time after that signal starts. It may also do the same for the secondoutput signal. The time periods, which may be in the range of 1 to 20second, more particularly 1 to 10 seconds are selected to providesufficient time for detection and recording by an outside receiver orthe controller itself, as well as conserve battery power.

The controller may also include logic in hardware or software forrecording and storing the start time and other information on the firstand second input signals such as their amplitudes. The controller mayalso include logic in hardware or software for calculating gastricemptying times (GET) or other GE parameter using approaches describedherein. For software implementations, the logic may be in the form of asoftware module resident in the controller (e.g., in RAM, ROM or othermemory) which includes algorithms calculation of GET. The same module,herein a GET module, may also be resident on controller on an externaldevice worn by the patient. In addition to calculation of GET by thesubtraction method described above, the module may include algorithmsfor calculation of GET which take into account other factors such as howlong it takes for the enteric coating to dissolve, and the amount, typeand time of any food eaten before, during or after the capsule wasingested. This information can be used to make allowances for longer orshorter gastric empting times for the type and amount of food eaten. Forexample, liquid vs solid meals and protein rich foods which leave thestomach sooner than foods high in carbohydrates, while food high inlipids (e.g., fat) take the longest to leave the stomach. In someembodiments, including those where GET calculation is done by acontroller on an external device, the patient may enter this information(e.g. using an external device such as a tablet, cell phone, etc.)including the nutritional information and portion size. The controller,including the module, may also include programming or other logic forcalculation of other GE parameters including one or more of, GEvelocity, the speed at which food/stomach contents moves from thestomach to the small intestine; average GE velocity, peak GE velocity,GET peristaltic contraction ratio; which is the ratio of GE time pernumber of peristaltic contractions; and GET average peristaltic forceratio, which is ratio of GET time per average force of peristalticcontraction occurring prior to or during the transit of food from thestomach to the small intestine.

However in other embodiments, including those where the GET module isresident in the controller on the capsule, a specific procedure can befollowed by the patient where the patient is given a test kit (herein aGET test kit) containing a capsule and a matched prepackaged GET testmeal having known parameters including for example a known portion sizeand known amounts of carbohydrates, protein, fat etc. These or othernutritional parameters comprise test meal information. The test mealinformation including portion size and nutritional information (e.g.,protein content etc.) are pre-entered into the GET module. The patientis also instructed to eat the meal with the capsule or at a set timeinterval before or after ingestion of the capsule. The test mealinformation may then be used by the GET module to adjust the measurementof GET accordingly (e.g., increase it or decrease it). For example, forhigher for larger and/or denser meals the GET module may decrease theultimately determined GET to reflect that the fact that denser foodsand/or larger portion sizes may take more time to move through thestomach. The converse being the case for smaller and/or less densemeals. In some embodiments, the capsule may actually be embedded orotherwise surrounded by the test meal, ensuring that both are takenconcurrently for embodiments where that is the desired approach.Embodiments using such a GET test kit provide the benefit of reducedvariability in gastric emptying due to the patient's eating habits andthus a more accurate result for GET or other GE parameter.

In another aspect, the invention provides a system for measurement ofGET or other GE parameter comprising embodiments of the swallowablecapsule described herein and an external receiver unit which may beconfigured to be worn or carried by the patient. The receiver unit willtypically include a receiver such as an RF receiver for receiving thetransmitted output and other signals by the capsule. The receiver unitmay also comprise and ultrasound receiver as well. It will also includea controller (e.g., a microprocessor) which may include hardware and/orsoftware such as a GET module for analyzing the transmitted signals fromthe capsule and determining GE times using one more approaches describedherein. The external receiver unit may also include audio alarms ordisplays for alerting the patient when capsule has reached the stomach(by detecting the first output signal) and when it has reached the smallintestine (by detecting the second output signal). The controller mayalso be programmed to display the calculated GE time or other GEparameter for use by the patient or medical provider.

In addition to the above features, the receiving unit may havecommunication ability itself for example, WIFI ability using a BLUETOOTHprotocol so as to allow for communication and data sharing with otherWIFI enabled devices such as cell phones, smart phones, tablets and thelike. In one implementation, the receiver unit can be configured tocommunicate and share data with a smart phone so that the patient canupload their GET and related data to their smart phone and then sendthat data over the INTERNET or other network to their physician or othermedical care provider.

In some embodiments, the receiver unit may comprise or be incorporatedinto an adhesive patch worn by the patient, for example, over theabdominal area to facilitate communication between the receiver and thecapsule. The patch may contain just the receiver or other components aswell such as the controller. The patch may also be configured towirelessly communicate with another external computational device suchas a tablet device or smart phone (e.g. by a BLUETOOTH protocoldescribed below) which receives information (e.g., information containedin the first or second signals) from the patch and performs variouscomputations to determine GE time or other GE parameter. Use of thepatch provides the benefit of improved signal receipt by the receiver(due to proximity) while still allowing the patient to see GE times andenter information, e.g., meal content and times.

In various embodiments, the enteric coating is selected to degrade inthe pH of the small intestine to expose the third electrode so that thethird electrode along with the second electrode electrically couple withthe contents in the small intestine to allow current to flow between thetwo electrodes. Also the coating can be configured to degrade within aselected portion of the small intestine based on pH. For example, inparticular embodiments, the coating can be configured to degrade above apH of about 5.5 for the duodenum or above a pH of 6.5 to 6.8 in thejejunum. In preferred embodiments, the coating is configured to degradeabove a pH of about 6.5. In various embodiments, the pH sensitivecoatings may correspond to EUDRAGIT coatings and others known in the artwhich degrade in response to specific pH's in specific location in theGI tract, such as more acid pH in the stomach (1.5-3.5) and increasinglyless acidic pH in the small intestine (5.5 in the duodenum and 6.5-6.8in the jejunum). In particular embodiments the EUDRAGIT coating isselected to degrade above a pH of about 6.5.

In yet another aspect, the invention provides a GET test kit includingan embodiment of the swallowable capsule described herein and a testmeal. The portion size and constituent components of the test meal(e.g., amount of fat, protein etc.) are preselected and matched to theparticular swallowable capsule, for example, in terms of size of capsuleand the positioning of the electrodes on the capsule. The nutritionalinformation and portion size of the test meal (described herein as testmeal information) can also be stored in memory of the capsulemicroprocessor or other controller so that that information can be usedin an algorithm for calculation of GE time or other GE parameter. Insome embodiments, the capsule and test meal are separate, while inothers the capsule is incorporated into the test meal either by beingsurrounded by the food material of the test meal or embedded or attachedto a surface of the test meal.

In yet another aspect, the invention provides various methods formeasuring GE time or other GE parameter using embodiments of theswallowable capsule described herein. In an exemplary embodiment of sucha method a patient for whom a GE parameter is to be measured ingests anembodiment of the swallowable capsule described configured to transmit afirst electrical signal when the capsule is in the stomach and a secondelectrical signal when the capsule is in the small intestine. Inparticular embodiments, this is accomplished using an embodiment of thecapsule having three electrodes positioned on its surface, the first andsecond electrodes being exposed and the third electrode covered by aninsulative pH sensitive coating which remains in the stomach butdegrades in the pH environment of the small intestine expose the thirdelectrode when in the small intestine.

When the capsule reaches the stomach, the first and second electrodeelectrically couple to fluids in the stomach and the first electricalsignal is generated and transmitted for detection and analysis by anexternal receiver unit or other device. At this point, the insulativecoating over the third electrode is still intact. However, when thecapsule reaches the small intestine the coating degrades to expose thethird electrode which along with the second electrode electricallycouples with the fluids in the small intestine to generate the secondelectrical signal which is transmitted. The first and second generatedsignals will typically be detected and analyzed by a receiver unit wornor otherwise in proximity to the patient. A gastric emptying parameter,such as GE time, is then determined using information from the first andsecond electrical signals. For gastric emptying time (GET) this is doneby subtracting the start time of the first signal from the start time ofthe second signal. This determination of GET can be done by logicresources resident on the external receiving device or the capsule. Therespective signals including their start times can also be used toprovide information on the location of the capsule including thelocation at a particular moment in time. For example, the start of thefirst signal provides information that the capsule has reached thestomach while the start of the second signal provides information thatthe capsule has reached the small intestine. The first and secondsignals can also be halted after a fixed interval, for example, aboutone to ten seconds in order to conserve power on the capsule includingbattery power. After the device enters the small intestine and thecoating degrades, it then passes through the digestive tract and iseliminated in the feces. Also, while the coating degrades, the capsuleshell does not and the capsule passes through the patient's intestinaltract intact. In some embodiments, the progress of the capsule can bemonitored using ultrasound imaging or fluoroscopy. In use, this approachprovides a verification of capsule location as determined from the firstand second signals. Further, location information from imaging may beused to develop a model to correlate signal generation locationinformation with a range of positions in the stomach or small intestine.Such a model may be used when doing subsequent GET tests without imagingto improve the accuracy of gastric emptying time calculation andcalculation of other GE parameters as well. In additional or alternativeembodiments, location information of the capsule may be determined usinga combination of RF and acoustic signals (detected from three or moreacoustic receivers placed on or near the patient's skin) to triangulatethe position of the capsule at a moment in time indicated by an RFsignal. Further description of apparatus, systems and methods fordetermination of capsule location using this approach may be found inone or more of U.S. Pat. Nos. 7,160,258, 8,005,536, 8,360,976,8,617,070, 9,167,990 and 9,456,774 which are incorporated by referencein their entirety for all purposes.

In particular embodiments of the invention, the methods and results frommeasuring GE time or other GE parameter can be used to diagnose apatient's gastroparesis or other like condition causing slow reducedmovement of food through the GI tract. GE time can be determined asdescribed above and then the determined time can be compared to a rangeof values for normal gastric emptying time and those for Gastroparesis.A determination can then be made if the patient has Gastroparesis basedon the comparison. In some embodiments, an algorithm for doing thecomparison can reside in a controller or other logic resources of theexternal receiver unit or another computing device. Typically, thealgorithm will be implemented by software by means of the GET module ora separate diagnostic module for performing Gastroparesis diagnosis. Anumber of GE tests can be run to improve the accuracy of the diagnosisparticularly, if the patient is in the borderline region between normalGE times and those for Gastroparesis. The diagnostic module may also useartificial intelligence and/or self-learning routines to look at poolsof patients and so improve the accuracy of diagnosis. It can also beused to assess the effectiveness of treatments for an individualpatient's Gastroparesis by looking at reductions and/or trends inreductions in the patient's GE times over the course of treatment.

In related embodiments, GE times determined by embodiments of theinvention can be used to help the patients with Gastroparesis or arelated disorder know when and how much of a subsequent portion of foodto eat after eating a first portion. In particular by knowing theirgastric emptying time, patients can time the consumption and amount of asecond or subsequent portion so they do not suffer from some of theadverse effects of Gastroparesis including nausea and vomiting sincethey will be allowing sufficient time for their stomach to empty beforethey eat their next portion. They can also use the GE time to controlthe size and nutritional content (e.g., fat, protein, carbohydrate etc.)of their initial portion as well since they know that fatty foods havelonger residence times in the stomach so they can make adjustmentsaccordingly in their subsequent portions. Algorithms, can be developedwhich use the patient's individual GE times, in particular thosedeveloped using embodiments of the test meal described herein (whichhave a known nutritional content) to make recommendations about timing,portion sizes and nutritional content of food to eat. The algorithm maybe contained in a software module embedded in thecontroller/microprocessor of the external receiver unit describedherein. The algorithm can be self-learning in that it can provide forinput from the patient on symptomology they are experiencing (e.g.nausea) after eating meals of known nutritional content, portion sizeand time after a previous meal. The algorithm then uses the symptomologyand meal information to tune or fine tune recommendations about portionssizes and timing between portions or meals.

In other embodiments, methods for measurement of GE times or other GEparameter can be incorporated into other medical uses. For example inone or more embodiment, measurement of GE time can be used to controladministration of therapeutics agents to the patient, includingadjustment of the dose and timing of administration. For the case ofdiabetics the measured GE times can be used to let them know when toadminister a dose of insulin or other glucose regulating agent after ameal since they will have good idea based on the GE time when theirblood glucose will rise after eating a meal. In use such, approacheshelps diabetics to better control their blood glucose levels withinnormal range since they can now time their insulin injection based onwhen they eat a meal. GE time can also be used to titrate the dose andtype of insulin or other glucose regulating agents. For example forslower times they may want to take a lower dose of insulin so that theydo not become too hypoglycemic and vice versa (e.g., higher doses forfaster GE-times so they do not become hyperglycemic). The recommendedadministration times can be incorporated into algorithms in softwaremodule of the receiving unit described herein. Other medications whichcan be so timed and adjusted include incretins such as various GLP-1incretins including, for example Exenatide, available under thetradename BYETTA. Other factors which can be used in conjunction with GEtimes in adjusting or titrating the dose and timing of the glucoseregulating compound can include the half-life of the particular glucoseregulating agent. So, for example, such agents having shorter half-livescan be taken sooner after eating a meal than those with longerhalf-lives.

Further details of these and other embodiments and aspects of theinvention are described more fully below, with reference to the attacheddrawing figures.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the present invention will now be discussed withreference to the appended drawings. It should be appreciated that thedrawings depict only typical embodiments of the invention and aretherefore not to be considered limiting in scope.

FIGS. 1A-1C illustrate different views and embodiments of theswallowable capsule of the present invention showing orientations ofsensing electrodes and enteric coatings.

FIG. 2A is a block diagram of exemplary sensing and receiving circuitryuseful in the devices and methods of the present invention.

FIG. 2B illustrates an exemplary layout of the circuitry of FIG. 2A inan embodiment of the capsule.

FIG. 3 illustrates external placement of a sensing patch on a patient'sabdomen in order to detect passage of a swallowable capsule of thepresent invention from the patient's stomach into the small intestine.

FIGS. 4A and 4B illustrate the progression of a swallowable capsule ofthe present invention through the patient's stomach into the smallintestines beyond the duodenum.

FIG. 5 illustrates the output signals and driver voltage produced by thecircuitry of FIGS. 2A and 2B.

FIGS. 6A and 6B illustrate embodiments of test kits for establishing abaseline gastric emptying time (GET) for individual patients.

FIG. 7 is a graph of velocity streamlines within the stomachillustrating the velocity fields within different areas of the stomachresulting from peristaltic contraction of the stomach including a flowcirculation (eddy) field in the corpus and a jet field in the antrumarea of the stomach.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention provide devices, systems andmethods for measuring a gastric emptying (GE) parameter (GEP), such as agastric emptying time (GET). Particular embodiments provide aswallowable capsule 10 having three or more electrodes E (E1, E2 and E3)with one of the electrodes covered by an enteric or other coating whichremains intact in the stomach but degrades in the small intestine (SI).The electrodes E are coupled to circuitry C such that when the capsuleis in the stomach, current flow occurs between the first two electrodesgenerating a first signal. In the small intestine, current flow occursbetween the second E2 and now uncovered third electrode and E3generating a second signal. These two signals can be transmitted andanalyzed externally or by an internal controller 60 to determine a GEP,e.g., a GET. The patient may wear an external device configured toreceive and analyze the signals to determine GET. Additional electrodesE may be included for generating additional signals to provideinformation for determination of a GET or other GEP such as the transittime of the capsule through the small intestine. Embodiments of theinvention may be used, for example, to diagnose gastroparesis and toprovide patients with information on when to eat meals or administerinsulin or other glucose regulating element after eating a meal.

Referring now to the drawings, FIGS. 1A-1C illustrate different viewsand embodiments of the swallowable capsule 10 of the present inventionshowing orientations of sensing electrodes and enteric coatings. Asshown in FIG. 1A, a swallowable capsule 10 comprises a capsule body 12having an exterior surface 14 (also referred to herein as an outer bodysurface) defining a capsule interior 13. The capsule body may befabricated from various biocompatible non toxic polymers known the inart which do not degrade in the stomach or other portion of the GItract. The capsule body 12 is desirably sized to pass easily from thestomach to the small intestine during gastric emptying and doesn't stayin the stomach too long (e.g., hours). In various embodiments, thecapsule size (when in oval or oval like shape) can be 00, 1, 2, 3, 4, or5 according to a standard capsule chart. In preferred embodiments thecapsule size is 4 or 5. Typically, capsule 10 will have an oval or ovallike shape but other shapes are also contemplated including circular,semicircular, cylindrical, pyramidal and rectangular with rounded edges.

First, second, and third electrodes E1, E2, and E3 have conductivesurfaces ES exposed on the exterior of the capsule body so thatimmersion of the capsule into an electrically conduce medium, such asthe fluids present in a patient's stomach and/or intestines, willprovide an electrically conductive bridge between the electrodes. Atleast one of the electrodes, and in some instances, two or three of theelectrodes, will initially be covered by an electrically insulatingcover, typically a coating 16, to electrically isolate pairs of theelectrodes (e.g., E2 and E3). Desirably, the coating is configured toprovide sufficient electrical resistance such that minimal or no currentflows between E3 and other electrodes when the coating is in place. Inparticular embodiments the coating may be configured to provide over 1mega ohm of resistance more preferably over 10 mega ohms of resistancebetween E3 and any other uncovered/uncoated electrode E.

The coating 16 or other cover is configured to selectively degrade inthe presence of the stomach and/or intestinal fluids. In particularembodiments, the pH-sensitivity of the coating is configured so that itwill remain intact when present in the stomach but degrade as the pHchanges (e.g., increases) after the capsule passes through the pylorusinto the small intestine. In this way, the coating 16 serves toselectively expose the third electrode E3 in the small intestine,allowing current to flow through circuit 2 and cause the generation ofoutput signal S2 which is used to determine when the capsule is in thesmall intestine. Put in another way, the coating 16 together withcircuits C1 and C2 function as a pH sensor for determination of whencapsule is in the stomach, small intestine or location in the GI tract(e.g., the large intestine).

The coatings for used for coating 16 which remain intact in the stomachbut are degraded in the small intestine are typically referred to asenteric coatings. In various embodiments, the enteric coating used forcoating 16 may correspond to copolymers derived from esters of acrylicand methacrylic acid (e.g. methacrylic acid-ethyl acrylate copolymers)made under the trade mark EUDRAGIT (available from the EVONIK IndustriesAG). The particular EUDRAGIT coating selected may be selected to degradeat a selected pH in the small intestine (5.5 in the duodenum, 6.5-6.8 inthe jejunum and 7-8 in the illeum). In particular embodiments, theEUDRAGIT coating is selected to degrade above a pH of about 6.5 to knowthat the capsule has fully entered the small intestine by being in themid portion of the small intestine (e.g., the jejunum) before the thirdelectrode E3 is exposed. According to additional or alternativeembodiments, coating 16 may comprise multiple coatings 16 which areplaced over one or more electrodes E and configured to degrade at aselected location in the small intestine. In use such embodiments allowfor the determination of transit times through specific sections of thesmall intestine. For example, according to one embodiment, coating 16may include a first coating configured to degrade at the pH at the entryof the duodenum (e.g., aground 5.5) exposing a third electrode (e.g. E3)and a second coating configured to degrade at the pH in the terminalileum (around 7.5 to 8) exposing a fourth electrode allowing for asignal to be generated by a third circuit. The particular coating 16 aswell as its thickness, can also be selected to have a known degradationtime at or above a selected particular pH, for example 10 to 15 minutes.In use, such embodiments of coatings 16 having known degradation timesimprove accuracy of the GET measurement by taking this degradation timeinto account in the GET or other GE parameter calculation. In variousembodiments, the thickness of coating 16 can be in a range from about0.001 to 0.1 inches with specific embodiments of 0.005, 0.01, 0.025,0.05, 0.075, 0.8 inches. The coating thickness can be selected based onone or more of the following: i) the amount of electrical resistancedesired between covered and uncovered electrodes, ii) the degradationtime of the coating in the small intestine or other GI tract location;and iii) the condition of the patient including their suspected degreeof gastroparesis Thicker coatings 16 can be selected for patients havinga greater degree of gastroparesis to provide a great amount ofprotection while the capsule is in the patient's stomach. Thickercoatings 16 can also be selected to provide increased amounts ofelectrical resistance between covered and uncovered electrodes. Theelectrical resistance of the coating 16 can also be increased throughthe use of biocompatible high resistance additives (e., those with ahigh dielectric constant) known in the art added to the methacrylicacid-ethyl acrylate copolymer or other coating.

As illustrated in the embodiment of FIG. 1A, electrode E3 is coveredwith the coating 16. After exposure to conditions within the smallsintestine, the coating will degrade, exposing E3 as shown in FIG. 1B.Thus, when the capsule 10 is initially swallowed and passes into thestomach, electrodes E1 and E2 will be exposed to the stomach liquids(e.g., acids) and will be in electrical contact (e.g., they will beelectrically shorted) via conductive fluids in the stomach such asstomach acid and partially digested food. When the capsule 10 furtherpasses into the intestines, the change in pH will degrade the coatingand electrode E3 will then be shorted with both electrodes E1 and E2. Asdescribed in more detail below, this change of state in the electricalcontact of the three electrodes will be used to generate signals thatallow the timing of passage of the capsule between the stomach and theintestines to be tracked.

As shown in FIGS. 1A and 1B, the electrodes 1A-1C are distributedaxially along the length 101 of the capsule and the coating covers oneend of the capsule over electrode E3. FIG. 1C show an alternativearrangement where electrodes E1-E3 are distributed circumferentiallyover the exterior 14 of the capsule body 12 and the coating 16 coversone side or lateral surface 141 s of the capsule exterior 14. Theelectrodes and the coating may be arranged in many other patterns, andmore than three electrodes and more than one coating and/or one coatingmaterial may be employed. For example, all electrodes could initially becovered with a coating or other barrier which degrades within thestomach to expose a first pair of electrodes to confirm passage into thestomach. One or more additional electrodes E could be covered by one ormore additional enteric coatings which degrade over different timesand/or in different regions of the gastrointestinal tract, e.g., thelarge intestine in order to provide information on transit times of thecapsule through a variety of locations in the GI tract. For example, twoadditional electrodes E positioned on the capsule body 12 could becovered by a second enteric coating which degrades in the largeintestine in order to confirm passage of the capsule from the smallintestine to the large intestine.

FIGS. 2A and 2B, depict example circuitry or circuits C includingcircuits C1 and C2 for measuring GET or other GEB by detectingelectrical shorting of the electrodes E1-E3. Typically, circuits C1 andC2 include an operational amplifier (opamp) OA, OA1 and OA2 respectivelyand at least three resistors R1, R2 and R3 respectively, which aredesireably arranged in a voltage divider configuration, though otherconfigurations contemplated. The opamp OA receives an input signal Infrom a node N of the respective circuit including the first or thirdelectrodes E1 and E3, amplifies it and then sends the output signal asan input signal IS to the controller 60. So for example, opamp OA1receives an input signal In1 from current flow CF1 from node N1, andopamp OA2 receives an input signal In2 from current flow CF3 from nodeN3. The voltages at each of the respective nodes N1, N2 and N3 aredesignated as V1, V2, and V3. The opamps OA1 and OA2 (or other opamp OC)may have gains from about 1 to 10,000 or larger, with specificembodiments of 100, 250, 500, 1000, 2500, 5000 and 7500. The gain can beselected based on the desired voltage of output signals S. Desirably,the resistances of R1 and R3 have a sufficiently high value so that nocurrent enters the body from the capsule body 12 other than through theelectrodes E. R2 also has a high value so that current entering the bodythrough electrodes E is minimal. In various embodiments, the resistanceof one more of R1, R2 and R3 have values greater than about 1 mega ohmand may be in a range from about 1 to 10 mega Ohm with higher valuesalso contemplated. Resistors R1, R2 and R3 may be fixed or variable. Inparticular embodiments, the use of digital potentiometers iscontemplated including for R2, where the resistance may be controlled bycontroller 60. The input voltage Vi for the circuits C1 and C2 isprovided via a driver input signal 61 resulting in current flow CF2 toelectrode E. According to one or more embodiments, driver signal 61 isprovided by controller 60, e.g., by a signal generator or opamp 62integral to controller 60 or other voltage source operably coupled toNode N2 and/or controller 60. One or both circuits of C1 and C2 may alsoinclude a capacitor (not shown) positioned in the circuit in a manner toensure that current that flows between the electrodes in the stomach orsmall intestine is an AC current.

In various embodiments, circuits C1 and C2 or other circuitry C, can beconfigured to perform one or more functions used in determining a GETfor a patient or other GE parameter. In particular embodiments, thefirst circuit C1 is configured to generate a first input signal IS1 whenthere is current flow between the first and second electrodes E1 and E2and the second circuit C2 is configured to generate a second inputsignal IS2 based when there is current flow between the second and thirdelectrodes E2 and E3. As is explained below, current flow occurs in thefirst circuit C1 when the first and second electrodes E1 and E2 comeinto contact with conductive fluids in the stomach such as stomachacids. When this happens, the first circuit C1 starts to generate aninput signal IS1 (converted by the processor to a first output signalS1) which provides an indication of when the capsule 10 has reached thestomach after being swallowed. Similarly, current flows in the secondcircuit C2 after the insulative coating 16 degrades in the smallintestine and the second and third electrodes E2 and E3 come intocontact with conductive fluids in the small intestine. When thishappens, the second circuit C2 generates an input signal IS2 (convertedto a second output signal S2) which provides an indication of when thecapsule 10 has reached the small intestine. Information from these twosignals IS1 and IS2 (or their corresponding output signals S1 and S2),including their start times, can then be used to determine gastricemptying time or another gastric emptying parameter. In particular, thestart time of the first input signal IS1 can be subtracted from thestart time of the second signal IS2 to arrive at a gastric emptyingtime. Similar calculations can be done for output signals S1 and S2,which can be configured by processor 60 to have the virtually the same(e.g., within a few hundredths or thousands of a second or less) starttimes as input signal IS1 and IS2. In various embodiments, thecalculation of GET (or other GE parameter) can be done by an externalcontroller (e.g., a processor) or the controller 60 (e.g., processor)within capsule 10. According to one embodiment, the calculation is doneby an external controller resident within an external receiver unit 30(described herein) or another external device such as a cell phone,tablet, and the like. In this approach, software or other logic residentwithin the external controller uses the start times (or otherinformation) of signals S1 and S2 (which are transmitted by the capsule)to perform the calculation of GET or other GE parameter. As is discussedbelow, signals S1 and S2 (or other output signal S) can be configured tobe distinct (e.g., via distinct frequencies such as distinctive chirpsignals described herein) so that they can be readily distinguished bysoftware or other logic resident within the external receiver or otherexternal device. In an additional or alternative embodiment, software orother logic resident within the controller on the capsule 10 can beconfigured to utilize the start time (or other information) of inputsignals IS1 and IS2 to make the calculation of GET or other GEparameter. In this approach, no distinction between the two signals isnecessarily needed as the signals IS1 and IS2 may be inputted to thecontroller via separate input channels on the controller (e.g., viainput channels on an A/D converter integral to or operatively coupled tothe controller). In an alternative approach, the start times of IS1 andIS2 can be stored in memory on board capsule 10 (e.g., RAM, DRAM, etc.integral or coupled to controller 60) and then be transmitted toreceiver unit 30 for processing by unit 30 or an external device 40 tocalculate GET or other GE parameter.

In particular approaches for calculation of GET, allowances can be madefor the estimated time it takes for the enteric coating 16 to degrade inthe small intestine (e.g., 10 to 15 minutes), as well as other factors(e.g., whether the capsule is taken with food, as well as the age,weight and size of the patient and/or other medications which may slowgastric emptying e.g., opiodes, calcium channel blockers or antidiarrhea drugs). Such allowances can be incorporated into a softwaremodule (such as modules 37 or 67 described below) or other logic fordetermination of gastric emptying time which may be resident on acontroller of an external device 40 or controller 60 in the capsule 10.

A discussion will now be presented on various aspects of controller 60.According to one or more embodiments, controller 60 may correspond to amicroprocessor, an analogue device, a state device, or other logicresources known in the art. For embodiments where controller 60corresponds to a microprocessor or other like device it will usuallyinclude one or more software modules 66, herein modules 66 includingelectronic instruction sets for performing one or more functions of thecontroller.

The controller 60 is operably coupled to circuitry C including one orboth of circuits C1 and C2 so that it may receive input signals IS1 andIS2. It is also operably coupled to a power source 70 such as a lithiumion or other miniature chemical storage battery known in the art. Inalternative embodiments, the use of micro super capacitors is alsocontemplated. It may also include or be operably coupled to atransmitter 80 such as an RF transmitter, for transmitting signals STencoding information from the controller, to a receiver on an externaldevice (e.g. receiver unit 30 or external device 40). In particularembodiments, transmitter 80 may transmit signals ST1 and ST2 encodinginformation on signals S1 and S2. In some embodiments, the controller 60may include a low power RF generator and the transmitter 80 maycorrespond to a power amplifier which amplifies the low power RF signalcoming from the controller. According to some embodiments, transmitter80 may also correspond to a receiver which may receive signals Sr fromunit 30 or device 40.

Controller 60 may be configured to perform a number functions either viahardware or software related to the determination of GET or other GEparameter. In particular, controller 60 may be configured to generateand/or utilize a clock signal 64 for determining the start times of thefirst and second input signals IS1 and IS2 so as to determine GET orother GE parameter. The clock signal may be single phase or multiphase(e.g., two phase or four phase). For embodiments where the controllercomprises a microprocessor can be generated by a clock signal generator65. According to other embodiments the clock signal can be generated byan analogue to digital converter which is integral to or operablycoupled to controller 60. As discussed above, in one or more embodimentscontroller 60 will also typically be configured to generate or otherwiseprovide a driver signal 61 sent to the second electrode E2 and receivesignals IS1 and IS2 from the first and second circuits when current isflowing through them in the stomach and/or small intestine. Generationof drive signal 61 can be done by software and/or hardware by a driveramplifier/generator 62 integral or otherwise operably coupled tocontroller 60. Typically, the driver signal 61 is in the form of an ACvoltage with low amperage in the milliamp range (e.g., 1-20), morepreferably in the micro-amp range (0.5 to 1 μa) and voltage in the rangefrom 0.5 to 2 volts with other ranges contemplated. Controller 60 isfurther configured to generate a first output signal S1 in response tothe first input signal IS1 from the first circuit and a second outputsignal S2 in response to the second input signal IS2 from the secondcircuit. The respective output signals will typically be in AC form andconfigured for transmission by the RF or other transmitter 80 integralto or otherwise coupled to the controller. These signals may begenerated by the controller itself or a signal generator electricallycoupled to the controller. In particular embodiments, the output signalssuch as S1 and S2 may correspond to distinctive chirp signals SC knownin the signal processing arts including first and second chirp signalsSC1 and SC2. In one particular embodiment, the first output signal maycorrespond to an up chirp signal SCU and the second signal to a downchirp signal SCD, the up chirp signal having a higher frequency then thedown chirp signal. The controller can also control how long a respectiveoutput signal is generated once it starts. For example, it can stop thefirst output signal S1 after a selected period of time after that signalstarts. It may also do the same for the second output signal. The timeperiods, which may be in the range of 1 to 20 seconds, more particularly1 to 10 seconds, are selected to provide sufficient time for detectionand recording by an outside receiver (e.g., receiver unit 30 describedherein) 60 or the controller itself, as well as to conserve batterypower.

In one or more embodiments the controller 60 may also be configured togenerate and transmit a tracking signal TS so as to know when thecapsule has been excreted from the patient's GI tract. Activation of thetracking signal may be based on detection of either input of signals IS1or IS2, with the tracking signal initiated at detection of the inputsignals or a select time period afterwards. The receiver unit 30 and/orexternal device 40 can be configured to detect the tracking signal andprovide status updates to the patient of detection or no detection ofthe tracking signal. In particular embodiments, unit 30 and/or externaldevice 40 can be programmed or otherwise configured to provide an alertto the patient of when capsule the capsule has been excreted based onfailure to detect the tracking signal for predetermined period of time(e.g., 5 to 10 minutes or longer). Unit 30 and/or external device canalso be programmed to use detection of the tracking signal to alert thepatient after that the capsule has remained in their GI tract anundesirable amount of time (e.g., longer than 24 hours). The patient maythen inform their doctor or take appropriate medication such as alaxative. In alternative or additional embodiments, capsule 10 mayinclude radio-opaque or echogenic markers 10 m in order to facilitatedetection of the capsule in the GI tract by fluoroscopy, ultrasound orother medical imaging modality.

As discussed herein, controller 60 may also include programming or otherlogic in hardware or software for recording and storing the start timeon the first and second input signals IS1 and IS2 well as otherinformation such as their amplitudes. Signals encoding this data canthen be transmitted to an external device by transmitter 80. Thecontroller 60 may further include logic in hardware or software forcalculating and analyzing gastric emptying times (GET) or other GEparameter using approaches described herein. For softwareimplementations, the logic may be in the form of a software module 67,herein module 67 resident in the controller (e.g., in RAM, DRAM, ROM,flash or other memory. Module 67 is also referred to herein as a GETmodule 67. The same module 67 (or one similar to it), may also beresident in the controller 35 of external receiver unit 30 worn by thepatient as is described below. In addition to calculation of GET by thesubtraction method described above, module 67 (as well as module 37) mayinclude algorithms for calculation of a GET which take into accountother factors such as how long it takes for the enteric coating todissolve as well as the amount, type and time of any food eaten before,during or after the capsule was ingested. This information can be usedto make allowances for longer or shorter gastric empting times for thetype and amount of food eaten. For example, liquid vs solid meals andprotein rich foods which leave the stomach sooner than foods high incarbohydrates, while food high in lipids (e.g., fat) take the longest toleave the stomach. In some embodiments, including those where GETcalculation is done by a controller on an external device 40 (e.g., acell phone, tablet or other portable computation device known in theart), the patient may enter this information including the nutritionalinformation and portion size into the external device. Controller 60,including module 67, may also include programming or other logic forcalculation of other GE parameters including one or more of thefollowing: GE velocity, the speed at which food/stomach contents movesfrom the stomach to the small intestine; average GE velocity, peak GEvelocity, GET peristaltic contraction ratio, the ratio of GE time pernumber of peristaltic contractions; and GET average peristaltic forceratio, the ratio of GET time per average force of peristalticcontraction occurring prior to or during the transit of food from thestomach to the small intestine.

In additional or alternative embodiments described below with respect toFIGS. 6a and 6b , a specific procedure can be followed by the patientwhere the patient is given a test kit 50 (herein at GET test kit)containing a capsule 10 and a matched prepackaged GET test meal 52having known a known portion size and known amounts of carbohydrates,protein, fat etc. The portion size and nutrition information of the testmeal comprise what is described herein as test meal information. Thetest meal information may be pre-entered into an embodiment of the GETmodule which for test meal embodiments will typically be resident oncapsule controller 60 (but may also be resident on the receiver unitcontroller 35). The patient is also instructed to eat the meal with thecapsule or at a set interval before or after ingestion of the capsule.In some embodiments, the capsule may actually be embedded or otherwisesurrounded by the test meal, ensuring that both are taken concurrentlyfor embodiments where that is the desired approach. Embodiments usingsuch a GET test kit 50 provide the benefit of reduced variability ingastric emptying due to the patient's eating habits and thus a moreaccurate result for GET or other GE parameter.

Referring now to FIG. 3, a receiver unit 30 for receiving signalstransmitted by capsule 10 encoding information on GET or other GEparameter may comprise and communicate with an adhesive patch 32 worn bythe patient (for example, over the abdominal area) to facilitatecommunication between the receiver and the capsule. Collectively,capsule 10, receiver unit 30 and patch 32 comprise a system 100 formeasurement of GET or other GE parameter. Receiver unit 30 may beincorporated into the patch or may be external to it and incommunication with circuitry carried by the patch to receive signalsfrom capsule 10. According to one embodiment where the receiver unit isexternal to the patch, patch 32 carries the circuitry necessary toreceive signals emitted by the capsule 10 and then transmits thosesignal to receiver unit 30 which carries the software application orother programming necessary to receive, process and optionally furthertransmit data to the cloud, physician, or elsewhere. Receiver unit 30will typically include a receiver 33, display 34, and a controller 35.Receiver 33 may correspond to an RF or other receiver known in themedical electronic arts. Controller 35 may correspond to amicroprocessor which may include (or have electronic access to) one ormore software modules 36 (herein modules 36) having logic for performingone or more operations including one or more of receiving, processingand transmitting signals S received from capsule 10 (e.g., signals S1and S2). In particular embodiments, modules 36 include a GET module 37which has logic for calculating GET or other GE parameter (e.g., smallintestine transit time) The controller 35 may also include a timerdevice 38 (in hardware or software) for timing the receipt of signals S1and S2 or other signal received from capsule 20. In particularembodiments, timer device 38 may correspond to a clock generator.

Patch 32 desirably corresponds to an adhesive patch configured to beworn over and adhere to the abdominal area of the patient so as toreceive signals S1 and S2 or signal from capsule 10. The patch 32 maycontain just the receiver unit 30 or other components as well. Forexample, according to one embodiment, all or a portion of the patch 32may comprise a conductive material 32C arranged as an antenna to improvethe reception of signals (e.g., S1 and S2) from capsule 10. Desirably,patch 32 is sufficiently flexible to bend and flex with movement of thepatients abdomen and stay adhered to the skin (with device 30 attached)so as to able to be able detect signals from the capsule 10 even whenthe patient is active or otherwise changes positions. This can beachieved by fabricating patch 32 from elastomeric polymers and skinadhesives known in the medical device and polymer arts. Also the patchcan be custom sized for a given patients abdomen (e.g., using 3^(rd)printing methods) to further improve adherence. Patch 32 includingreceiver unit 30 may also be configured to wirelessly communicate (e.g.by a BLUETOOTH protocol described with another external communicationsdevice 40 such as a tablet device or smart phone which receivesinformation (e.g., information contained in the first or second signals)from the patch and performs various computations to determine GE time orother GE parameter. While the capsule could communicate directly withthe communication device 40, use of the patch 32 provides the benefit ofimproved signal receipt by device 30 (due to proximity) while stillallowing the patient to easily see displayed GE times and enterinformation, e.g., meal content and times on the communication deviceonto the external.

Referring now to FIGS. 4A and 4B, an embodiment of a method of using thecapsule 10 to measure GET (or other GE parameter) will now beillustrated. After the patient swallows an embodiment of capsule 10 itpasses from the esophagus into the stomach. Once there the stomachcontents (e.g acids) provide a conductive pathway between the first andsecond electrodes E1 and E2 so there is current flow in the firstcircuit. This results in the generation and transmission of the S1output signal. At this point, the insulative coating 16 over the thirdelectrode E3 is still intact and there is no current flow in the secondcircuit and no generation of the S2 output signal. However, when capsule10 reaches the small intestine, coating 16 degrades to expose the thirdelectrode E3 which along with the second electrode electrically coupleswith the conductive fluids in the small intestine resulting in thecurrent flow in the second circuit and the generation and transmissionof the S2 output signal After passage out of the small intestine, thecapsule enters the large intestine and is excreted out of the patient'sbody. In embodiments employing a tracking signal described herein,excretion of the capsule may be determined by loss of detection of thetracking signal TS by receiver unit 30. In embodiments having additionalcoatings 16 and electrodes E, additional output signals may be generatedwhen the capsule reaches another selected location in the GI tract, suchas the large intestine or the ileum portion of the small intestine. Thepatient may repeat the above procedure multiple times after excretion ofa prior capsule in order to have multiple determinations of GET so asprovide the physician with precision and other statistical metrics of aGET measurement. In particular the patient may take the pill at the sameor different times over the day as well with or without food to accountfor affects due to circadian rhythm and diet. The patient may alsorepeat the above GET measurement procedure after a gastroparesistreatment has begun (e.g., the use of drugs or the implantation of agastric pacemaker known in the art) in order to assess treatmentefficacy and target endpoints as well as titrate the dosage of a drug orother therapeutic agent. The described GET measurement method may alsobe performed concurrently or nearly currently with a traditional GETmeasurement procedure (e.g. by swallowing a contrast agent andperforming fluoroscopy) in order to provide a comparison between the twomethods and if necessary calibrate the measurements made using thedescribed methods to those of the traditional methods. According someembodiment the calibration can be done via software using one or moreembodiments of the GET software module (e.g., modules 37 or 67).

Referring now to FIG. 5, a discussion will be presented of the signalsand functions of the circuitry of the embodiments of FIGS. 2A and 2B. Asdiscussed herein, the circuitry typically includes a controller 60 whichamong other functions generates or processes one or more of the signalsin circuitry C including circuits C1 and C2. In various embodiments, itmay be configured to generate a driver signal 61, sent to the secondelectrode E2 and receive signals (e.g., input signals IS1 and IS2) fromthe first and second circuits C1 and C2 when current is flowing throughthem. Typically, the driver signal 61 is in the form of an AC voltagewith very low amperage in the milliamp range (e.g., 1-20 milliamps) andvoltage in the range from 0.5 to 2 volts with other ranges contemplated.Controller 60 is further configured to generate a first output signal S1in response to the first input signal IS1 from the first circuit and asecond output signal S2 in response to the second output signal from thesecond circuit. The respective output signals S1 and S2 will typicallybe in AC form and configured for transmission by the RF or othertransmitter (e.g., acoustic) integral to or otherwise coupled to thecontroller. Desirably, the first and second output signals S1 and S2 areconfigured to have distinct frequencies (or other waveformcharacteristic) to facilitate their individual detection, e.g., by thereceiver unit 30 or like device. According to one or more embodimentssignals S1 and S2 are configured as chirp signals SC known in theelectronic and signal processing arts. In one particular embodiment, thefirst output signal S1 may correspond to an up chirp signal SU (in whichthe frequency increases) and the second signal S2 a down chirp signal(in which the frequency decreases). These signals may be generated bycontroller 60 itself or a signal generator electrically coupled to thecontroller.

In addition to use of distinctive chirp signals, other means arecontemplated for determining when capsule 10 has reached the smallintestine. For example as shown in FIG. 6, S1 will typically decrease inamplitude once the capsule reaches the small intestine due to thevoltage divider arrangement of electrodes E1, E2 and E3. This decreaseis specifically illustrated by the decrease in amplitude going fromsection S1 a to section S1 b of the S1 waveform shown in FIG. 6. Assuch, controller 35 on unit 30 or a controller on external device 40 orcontroller 60 can be configured to detect the decrease. The controller60 may also control how long a respective output signal is generatedonce it starts. For example, it can stop the first output signal S1after a selected period of time after that signal starts. It may also dothe same for the second output signal. The time periods, which may be inthe range of about 1 to 10 seconds, are selected to provide sufficienttime for detection and recording by communication device 30 or thecontroller itself. In particular embodiments, the first output signal isstopped soon after initial detection by the receiver unit 30 in order tofacilitate detection of the initiation of the second output signal,e.g., so there is no possible confusion between the two signals by unit30 or external communication device 40.

Referring now to FIGS. 6A and 6B, in one or more embodiments of theinvention a test kit may utilized for establishing a baseline gastricemptying time (GET) for individual patients. Baseline GET being thatwhere the patient eats a fixed quantity of food having known anutritional content (e.g. a known amount of fat, protein carbohydrates,herein referred to as nutritional information) to reduce variability inGETs occurring for different meal nutritional content and meal size.Collectively, this information is referred to as nutritionalinformation. According to one embodiment, a GET test kit 50 may includethe capsule 10 and a matched prepackaged GET test meal 52 having a knownportion size known amounts of carbohydrates, protein, fat etc.,typically in a sterile pack or package 54. These and other parametersand characteristics of the test meal are known as test meal information.Such test meal information may be pre-entered into the GET moduleresident on the controller of the capsule 10, receiver device 30 or anexternal device 40. The test meal information may then be used to adjustthe final determined value for GET accordingly. For example, GE timescan be decreased for higher protein and/or denser meals which may takemore take to travel from the stomach to the small intestine. The reversebeing the case for less dense and/or low protein content meals. The kitswill typically also include instructions 56 for the patient to eat themeal with the capsule or at a set interval before or after ingestion ofcapsule 10. As shown in FIG. 6B, in an alternative embodiment, thecapsule 10 may actually be embedded or otherwise surrounded by the testmeal 52 so as to compromise a capsule embedded test meal 53. Embodimentsof such a capsule embedded test meal 53 ensuring that the both are takenconcurrently for embodiments where that is the desired approach. Ineither case, embodiments using a GET test kit 50 including a test mealprovide the benefit of reduced variability in GET or other GE parametermeasurement due to the patient's eating habits and thus provide a moreaccurate and reproducible result for GET or other desired GE parameter.

In various embodiments, the physical properties of capsule 10 can beconfigured to facilitate passage of the capsule through the stomach inthe same manner and/or at the same rate as food so as to more accuratelypredict GET or other GE parameter. For example, according to one or moreembodiments, the density of the capsule may be configured to approximatethat of typical stomach contents with food present which isapproximately lgr/cc (per the article by MJ Ferrua et al., referencedbelow. When capsule 10 has such a density, the capsule neither floats atthe top nor sinks to the bottom of the stomach when it contains food.Rather, it passes through the stomach in the same manner and at the samerate as digested or partially digested food. Also, if taken with food,the capsule will pass through the stomach along with the bulk of thedigested food contents (also in the stomach) and in the same timeinterval as the food contents. In use, embodiments of the inventionhaving a capsule so configured provide the benefit of a more accuratemeasurement of gastric emptying time or other gastric emptying parameterfor digested food since the capsule mimics the density of digested foodin the stomach. A range of capsule densities is also contemplated forexample 0.5 to 1.5 mg/cc, with higher or lower density selecteddepending upon the condition of patient and/or the size and contents ofa test meal (described below) taken along with capsule. Obtaining aspecific capsule density can be achieved by selection of the capsulebody materials as wells as the components and filler material placed inthe capsule body. The filler material may comprise various biocompatiblepolymeric material known in the art including polymer gels.

In particular embodiments, the density of the capsule can be matched tothat of the composition/content of the test meal. So for example, higherdensities (e.g. >1.0 ml/cc, 1.1 to 1.5 ml/cc) for the capsule may beused with more dense test meals (e.g., those containing more protein)and lower densities (e.g. <1.0 ml/cc, 0.5 to 0.9 ml/cc) may be used forless dense test meals (e.g. bread), and moderate (e.g., 1densities maybe used for moderate dense meals which approximate the density of water,e.g., milk shakes soup etc. Further information on the densities ofstomach contents as well as the motility pattern and velocity profilesand patterns within the stomach including the pylorus may be found inthe article by MJ Ferrua et al. entitled, Modeling the Fluid Dynamics ina Human Stomach to Gain Insight of Food Digestion, Food Sci. 2010September; 75(7): R151-R162, which is incorporated by reference hereinfor all purposes.

In other embodiments, the shape of the capsule can be selected for theparticular velocity field or profile within particular portions of thestomach such that capsule is advanced or remains within that portion forperiod of time before being advanced. Referring now to FIG. 7, as knownin the art (e.g., the paper by Ferrua et al.) there are two velocityfields created in the stomach by peristaltic motion these include arecirculation or eddy field (EF) in the Corpus portion C of the stomachwhich is low velocity and a high velocity or jet field (JF), alsodescribed as a retro-pulsive jet field, in the stomach antrum portion Aof the stomach. Accordingly, in one embodiment an elongated shapedcapsule (e.g., oval, cylindrical etc.) can be used so that the capsuleis readily picked up and transported from the eddy field to theretro-pulsive jet field. Alternatively in another embodiment, aspherical shaped capsule can be employed when it is desired the capsuleremain in the eddy field for longer periods of time. Other shapes arealso contemplated to facilitate retention in the eddy field or transferof the capsule between from the eddy field to the retro-pulsive jetfield.

In still other embodiments, the surface tension of the outer surface ofcapsule 12 body can configured to be in the same range as that of thegastric juices/liquid content of the stomach such that the gastricjuices readily wet the surface of the capsule body. In variousembodiments this surface tension (i.e., the air liquid surface tensioncan range from about 30 to about 45 dynes/cm with a specific values of30.5, 33, 35, 36.8 38, 40, 42, 43 and 44 dynes/cm. For embodiments wherethe capsule is taken with food such as with test meal 52 the capsulebody can have a surface tension in the range of about 28 to 32 dynes/cmwith specific values of 30 and 30.5 and 31 dynes/com. Approaches forobtaining such surface tensions can include the use of biocompatiblepolymers and polymeric coatings known in the art having the desiredsurface tension. For example in one or more embodiments capsule body 12may comprise one or more forms of polyethylene which has surfacetensions in the range of 35 to 36 dynes/cm or polyethylene teraphalatewhich has surface tension of about 42 dynes/cm. Other approaches mayinclude the use of surface treatments such as various plasma treatmentand other chemical treatments known in the polymer and surface treatmentarts.

In use, such embodiments of capsule body 10 having one of theaforementioned surface tensions, allow for the capsule 10 to be readilycarried by and flow with the liquid digested contents of the stomach asthey are propelled and otherwise move through the stomach fromperistaltic contraction or other related digestive motion. This in turn,allows movement of the capsule through the stomach to more accuratelyreflect the movement of digested liquid food contents through thestomach providing for more accurate measurement of GE time or other GEparameter.

Method for Diagnosis of Gastroparesis

In various embodiments of the invention, results from measuring GE timeor other GE parameter obtained from using embodiments of swallowablecapsule 10 can be used to diagnose a patient's gastroparesis or otherlike condition causing slow reduced movement of food through the GItract. GE time can be determined as described above and then thedetermined time can be compared to a range of values for normal gastricemptying time and those for Gastroparesis. A determination can then bemade if the patient has Gastroparesis based on the comparison. In someembodiments, an algorithm for doing the comparison can reside in acontroller or other logic resources of the external receiver unit oranother computing device. Typically, the algorithm will be implementedby software by means of the GET module or a separate diagnostic modulefor performing Gastroparesis diagnosis. A number of GE tests can be runto improve the accuracy of the diagnosis particularly, if the patient isin the borderline region between normal GE times and those forGastroparesis. The diagnostic module may also use artificialintelligence and/or self-learning routines to look at pools of patientsand so improve the accuracy of diagnosis. It can also be used to assessthe effectiveness of treatments for an individual patient'sGastroparesis by looking at reductions and/or trends in reductions inthe patient's GE times over the course of treatment.

Use of Gastric Emptying Time for Timing of Meal Consumption

In related embodiments, GE times determined by embodiments of theinvention can be used to help the patients with Gastroparesis or arelated disorder know when and how much of a subsequent portion of foodto eat after eating a first portion. In particular by knowing theirgastric emptying time, patients can time the consumption and amount of asecond or subsequent portion so they do not suffer from some of theadverse effects of Gastroparesis including nausea and vomiting sincethey will be allowing sufficient time for their stomach to empty beforethey eat their next portion. They can also use the GE time to controlthe size and nutritional content (e.g., fat, protein, carbohydrate etc.)of their initial portion as well since they know that fatty foods havelonger residence times in the stomach so they can make adjustmentsaccordingly in their subsequent portions. Algorithms, can be developedwhich use the patient's individual GE times, in particular thosedeveloped using embodiments of the test meal described herein (whichhave a known nutritional content) to make recommendations about timing,portion sizes and nutritional content of food to eat. The algorithm maybe contained in a software module embedded in thecontroller/microprocessor of the external receiver unit describedherein. The algorithm can be self-learning in that it can provide forinput from the patient on symptomology they are experiencing (e.g.nausea) after eating meals of known nutritional content, portion sizeand time after a previous meal. The algorithm then uses the symptomologyand meal information to tune or fine tune recommendations about portionssizes and timing between portions or meals.

In other embodiments, methods for measurement of GE times or other GEparameter can be incorporated into other medical uses. For example inone or more embodiment, measurement of GE time can be used to controladministration of therapeutics agents to the patient, includingadjustment of the dose and timing of administration. For the case ofdiabetics the measured GE times can be used to let them know when toadminister a dose of insulin or other glucose regulating agent after ameal since they will have good idea based on the GE time when theirblood glucose will rise after eating a meal. In use such, approacheshelps diabetics to better control their blood glucose levels withinnormal range since they can now time their insulin injection based onwhen they eat a meal. GE time can also be used to titrate the dose andtype of insulin or other glucose regulating agents. For example forslower times they may want to take a lower dose of insulin so that theydo not become too hypoglycemic and vice versa (e.g., higher doses forfaster GE-times so they do not become hyperglycemic). The recommendedadministration times can be incorporated into algorithms in softwaremodule of the receiving unit described herein. Other medications whichcan be so timed and adjusted include incretins such as various GLP-1incretins including, for example Exenatide, available under thetradename BYETTA. Other factors which can be used in conjunction with GEtimes in adjusting or titrating the dose and timing of the glucoseregulating compound can include the half-life of the particular glucoseregulating agent. So, for example, such agents having shorter half-livescan be taken sooner after eating a meal than those with longerhalf-lives.

Additional GE Parameters and their Uses

In addition to measurement of Gastric Emptying time, embodiments of theinvention also contemplate measure of a number of other Gastric Emptyingand other GI tract related parameters. These parameters include one ormore of the following: GE velocity, the speed at which food/stomachcontents moves from the stomach to the small intestine; average GEvelocity; peak GE velocity; number of peristaltic contractions occurringin the stomach and/or small intestine which are exerted on thecapsule/food during gastric emptying; GET to peristaltic contractionratio; which is the ratio of GE time per number of peristalticcontractions; average and peak peristaltic forces exerted by the stomachand/or small intestine on capsule/food during the transit of food fromthe stomach to the small intestine; and GET to average peristaltic forceratio, which is ratio of GET per average force of peristalticcontraction occurring prior to or during the transit of food from thestomach to the small intestine. The determination of theses parametersmay be done by programming (e.g., software modules) or other logicresident in a controller on the capsule (e.g., controller 60) or theexternal receiving device (e.g., controller 35). Measurement of GEvelocity may be facilitated by including one or more sensors 10S on orin capsule 10 for making various measurements as shown in FIGS. 1A, 1 band 2 b. In various embodiments, sensor 10S may correspond to anaccelerometer for providing velocity and acceleration data of thecapsule in the GI tract; and a force sensor such as a strain gauge forproviding data including the magnitude of peristaltic forces exerted onthe capsule as well as the number of peristaltic contractions exerted onthe capsule during gastric emptying or other period of time in thedigestive period. The output of these sensors can be coupled tocontroller 60 and/or transmitter 80 which then generate a signalencoding measured data by the sensors (e.g. force, velocity, etc.) fortransmission to receiver 33 on the receiver unit 30 or other externalreceiving device, e.g., device 40. These and other GE parameters can beused for one or more of the following clinical applications: i)diagnosis of gastroparesis or other like condition; ii) diagnosis ofirritable bowel syndrome by an above average number of peristalticcontractions and/or increase in GE velocities; iii) providinginformation that the patient may use to titrate or adjust the timing anddose of the administration of medication before, during or after eatinga meal; iv) providing information that the patient may use to titrate oradjust the timing and dose of insulin or other glucose regulatingbefore, during or after eating a meal so that they may obtain improvedcontrol of their blood sugar levels and reducing the occurrence ofhypoglycemia and hyperglycemia; and iv) providing information that thepatient may use to titrate or adjust the timing and/or portion size of ameal particularly after a first or other prior meal or portion is eaten.Timing in this case being the time after a eating a prior meal orportion.

CONCLUSION

The foregoing description of various embodiments of the invention hasbeen presented for purposes of illustration and description. It is notintended to limit the invention to the precise forms disclosed. Manymodifications, variations and refinements will be apparent topractitioners skilled in the art. For example, the capsule can be sizedand otherwise configured for various pediatric applications. Also, insome embodiments, the capsule coating can be configured to degrade inthe large intestine so that transit times from the stomach to the largeintestine can be measured. Further, in some embodiments, the capsule caninclude four electrodes with the third covered by a coating thatdegrades in the small intestine and a fourth which degrades in the largeintestine so that transit times from the small to the large intestinecan be measured. In use, such embodiments provide the clinician has alinear map of transit times between specific organs within the GI tractas well overall transit times. Additionally, various embodiments of thecapsule can include two way telemetry for signaling to and from anexternal monitoring and/or control device, such as embodiments of thereceiving device described herein. Also, in alternative embodiments, inplace of electrodes, the capsule may includes a pH sensor fordetermining where the capsule is in the intestinal tract based on the pHin the respective location (e.g., the stomach or small intestine). Sofor example, a pH reading in the range of about 1.5 to 3.5 wouldindicate the capsule was in the stomach and a pH of above about 6 or 6.5would indicate the capsule is in the small intestine.

Elements, characteristics, or acts from one embodiment can be readilyrecombined or substituted with one or more elements, characteristics oracts from other embodiments to form numerous additional embodimentswithin the scope of the invention. Moreover, elements that are shown ordescribed as being combined with other elements, can, in variousembodiments, exist as standalone elements. Further still, it should beappreciated that every recitation of an element, component, compound,value, characteristic or acts, also means that embodiments arecontemplated which specifically excludes those elements, components,compounds, etc. Hence, the scope of the present invention is not limitedto the specifics of the described embodiments, but is instead limitedsolely by the appended claims.

1. (canceled)
 2. A swallowable capsule for measurement of a gastric emptying parameter in a gastro-intestinal (GI) tract of a patient, the capsule comprising: a first, second, and third electrode; a first circuit electrically coupled to the first and second electrodes, the first circuit configured to generate a first input signal based on a current flow between the first and second electrodes at a first location in the GI tract; a second circuit electrically coupled to the second and third electrodes, the second circuit configured to generate a second input signal based on a current flow between the second and third electrodes at a second location in the GI tract different from the first location; and a controller operatively coupled to the first and second circuits, wherein the controller is programmed to determine the gastric emptying parameter based on information relating to the first and second input signals.
 3. The capsule of claim 2, wherein the first location is the stomach and the second location is the small intestine.
 4. The capsule of claim 3, further comprising an enteric coating disposed over the third electrode, the coating configured to electrically insulate the third electrode while in the stomach and degrade in response to a selected pH in the small intestine to expose the third electrode.
 5. The capsule of claim 2, wherein the controller is further programmed to generate and transmit a driver signal to the second electrode so as to provide the current flow between the first and second electrodes and the current flow between the second and third electrodes.
 6. The capsule of claim 5, wherein the driver signal is an alternating current (AC) signal.
 7. The capsule of claim 2, further comprising a transmitter coupled to or integral with the controller.
 8. The capsule of claim 7, wherein the transmitter is a radiofrequency (RF) transmitter.
 9. The capsule of claim 2, wherein the information relating to the first and second input signals is a start time of the first input signal and a start time of the second input signal.
 10. The capsule of claim 9, wherein the controller is further programmed to determine a gastric emptying time based on a difference between the start time of the first input signal and the start time of the second input signal.
 11. A swallowable capsule for measurement of a gastric emptying parameter in a gastro-intestinal (GI) tract of a patient, the capsule comprising: a first, second, and third electrode; a first circuit electrically coupled to the first and second electrodes, the first circuit configured to generate a first input signal based on a current flow between the first and second electrodes at a first location in the GI tract; a second circuit electrically coupled to the second and third electrodes, the second circuit configured to generate a second input signal based on a current flow between the second and third electrodes at a second location in the GI tract different from the first location; a controller operatively coupled to the first and second circuits, wherein the controller is programmed to generate a first output signal in response to the first input signal and a second output signal in response to the second input signal; and a transmitter configured to transmit the first and second output signals to an external controller to determine the gastric emptying parameter based on information relating to the first and second output signals.
 12. The capsule of claim 11, wherein the controller is further programmed to generate and transmit a driver signal to the second electrode so as to provide the current flow between the first and second electrodes and the current flow between the second and third electrodes.
 13. The capsule of claim 12, wherein the driver signal is an alternating current (AC) signal.
 14. The capsule of claim 11, wherein the transmitter is a radiofrequency (RF) transmitter.
 15. The capsule of claim 11, wherein the first location is the stomach and the second location is the small intestine.
 16. A system for measuring a gastric emptying parameter, the system comprising: the capsule of claim 11; and a receiver unit for receiving the transmitted first and second output signals.
 17. The system of claim 16, wherein the receiver unit comprises the external controller of claim 11, and wherein information relating to the first and second output signals is a start time of the first output signal and a start time of the second output signal, respectively.
 18. The system of claim 17, wherein the external controller is programmed to determine a gastric emptying time based on a difference between the start time of the first output signal and the start time of the second output signal.
 19. A swallowable capsule for measurement of a gastric emptying parameter in a gastro-intestinal (GI) tract of a patient, the capsule comprising: a first, second, and third electrode; and a first circuit electrically coupled to the first and second electrodes, the first circuit configured to generate a first input signal based on a current flow between the first and second electrodes at a first location in the GI tract; a second circuit electrically coupled to the second and third electrodes, the second circuit configured to generate a second input signal based on a current flow between the second and third electrodes at a second location in the GI tract different from the first location; and a controller programmed to: generate and transmit a driver signal to the second electrode so as to provide the current flow between the first and second electrodes and the current flow between the second and third electrodes; and generate a first output signal in response to the first input signal and a second output signal in response to the second input signal.
 20. The capsule of claim 19, wherein the controller is further programmed to determine the gastric emptying parameter based on information relating to the first and second input signals.
 21. The capsule of claim 19, further comprising a transmitter configured to transmit the first and second output signals to an external controller to determine the gastric emptying parameter based on information relating to the first and second output signals. 